During
infections with the protozoan parasite Toxoplasma gondii,
gamma-aminobutyric acid (
GABA) is utilized as a
carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for
GABA, however, is its role in the nervous system as an inhibitory
neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered,
seizures develop. Human
toxoplasmosis patients suffer from
seizures, suggesting that Toxoplasma interferes with
GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic
proteins appeared normal,
infection with type II ME49 Toxoplasma tissue
cysts led to global changes in the distribution of
glutamic acid decarboxylase 67 (GAD67), a key
enzyme that catalyzes
GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous
seizures and are more susceptible to drugs that induce
seizures by antagonizing
GABA receptors. Interestingly, GABAergic
protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which
seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling.
IMPORTANCE:
Infections of the central nervous system can cause
seizures. While
inflammation in the brain has been proposed to initiate the onset of the
seizures, relatively little is known about how
inflammation impacts the structure and function of the neurons. Here we used a parasite called Toxoplasma gondii that infects the brain and showed that
seizures arise due to a defect in signaling of
GABA, which is the
neurotransmitter primarily responsible for preventing the onset of
seizures.